1. Technical Field
The present invention generally relates to a process for the preparation of a fosaprepitant dimeglumine intermediate and its use in the preparation of fosaprepitant dimeglumine; to a neutral form of fosaprepitant, more specifically in a solid state and processes for the preparation thereof; and to a stable amorphous fosaprepitant dimeglumine and a process for the preparation thereof.
2. Description of the Related Art
Fosaprepitant dimeglumine is approved for the treatment of emesis, nausea, cancer therapy toxicity and is available in the market by brand name EMEND® in the US and IVEMEND® in Europe, with the dosage strength 115 mg equivalent base.
Fosaprepitant dimeglumine is chemically known as 1-deoxy-1-(methyl amino)-D-glucitol[3-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-2,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]phosphonate (2:1) (salt) and is structurally represented by formula (I):

US Publication 20070265442 describes a process for the preparation of fosaprepitant dimeglumine using monobenzyl ester fosaprepitant as an intermediate; but it neither discloses nor characterizes the polymorph obtained.
U.S. Pat. No. 5,691,336 describes morpholine compounds including fosaprepitant and its pharmaceutically acceptable salts thereof. The U.S. '336 patent exemplifies the process for the preparation of fosaprepitant dimeglumine as amorphous powder by lyophilization of an aqueous solution.
Fosaprepitant in solid state, isolated form has not been reported in the literature as of date. Also polymorphs of fosaprepitant neutral form have not been reported in the literature.
The difference in the physical properties of different solid state forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula, while having distinct physical properties, which may be advantageous relative to other solid state forms of the same compound or complex.
The discovery of fosaprepitant in solid state provides a new opportunity to improve the performance of the active pharmaceutical ingredient (API), fosaprepitant dimeglumine or other salts, by producing solid forms of pure fosaprepitant having improved characteristics, such as stability, flowability, and solubility. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Thus, there is a need in the art to provide fosaprepitant in solid state and possible polymorphic forms of fosaprepitant. The availability of neutral fosaprepitant in solid form would be an added advantage in the preparation of pharmaceutically acceptable salts of fosaprepitant such as fosaprepitant dimeglumine useful in the preparation of pharmaceutical formulations, particularly parental dosage forms for the treatment of emesis, nausea, cancer therapy toxicity.